DESCRIPTION: GABA-A-receptor-mediated responses provide delicate inhibitory control of excitatory systems in the mammalian brain and are themselves subject to other controls. During the previous grant period the applicant described a new mechanism of regulation of GABA-A responses in the hippocampus. This mechanism, which they call depolarization- induced suppression of inhibition, DSI, is unique in implying that a pyramidal cell can influence its own inhibitory input and that this influence may involve a retrograde signal that decreases GABA release from interneurons. A unique feature of hippocampal DSI is its marked potentiation by muscarinic receptor activation. Because of the numerous physiological implications of DSI, the applicant proposes to investigate it in detail during the next grant period. They will use whole-cell electrophysiological recording techniques in the in vitro hippocampal slice to test the central hypothesis that grew out of work done in the previous grant period. The main hypothesis is that Ca2+ entering pyramidal cells through voltage-dependent Ca2+ channels initiates the induction of a retrograde signal that diffuses to interneurons and prevents their release of GABA. Specific aims of the proposal address components of this hypothesis. The applicants propose to determine (1) if a retrograde signal in fact mediates DSI, (2) how DSI is induced, (3) what role muscarinic receptors play in enhancing DSI and (4) whether DSI regulates cellular excitability and whether it can be produced by endogenous cell firing. The classical chemical synapse is unidirectional; signals pass from the pre- to the post-synaptic cell in the anterograde direction. Retrograde signaling implies traffic in the opposite direction. Although this is a relatively new concept, supporting evidence for it has already been found in several systems. DSI, which occurs in hippocampus and cerebellum, appears to be the first case of retrograde signaling in the GABA system. In view of the widespread regulatory influence of GABA in both normal and diseased states, this new control mechanism is likely to be significant.